L-3-hydroxymethyltyrosine and salts thereof

ABSTRACT

The compound L-3-hydroxymethyltyrosine is a chelating agent for heavy metal ions and possesses antihypertensive activity. A process is disclosed for making optically pure L-3hydroxymethyltyrosine.

Unite States atent 1 Suh et al.

[ *Sept. 9, 1975 L-3-HYDROXYMETHYLTYROSINE AND SALTS THEREOF Inventors: John T. Suh, Mequon; Richard A.

Schnettler, Brown Deer, both of Wis.

Assignee: Colgate-Palmolive Company, New

York, NY.

The portion of the term of this patent subsequent to July 23, 1991, has been disclaimed.

Filed: Dec. 22, 1972 Appl. No.: 317,800

Notice:

UNITED STATES PATENTS 7/l97l Reinhold et al. 260/519 OTHER PUBLICATIONS Gilman, Organic Chemistry, Vol. 1, 2nd ed., (1958), pp. 803-805.

Dauben et al., Journal of the American Society, Vol. 70, (1948), PP. l759l762.

Chemical Abstracts, Vol. 42, 1311).

Primary Examiner.lames A. Patten Assistant Examiner-L. A. Thaxton Attorney, Agent,0r FirmT. F. Kryshak; M. L. Youngs [5 7] ABSTRACT The compound L-3-hydroxymethyltyrosine is a chelating agent for heavy metal ions and possesses antihypertensive activity. A process is disclosed for making optically pure L-3-hydr0xymethyltyrosine.

2 Claims, No Drawings L-3-HYDROXYMETHYLTYROSINE AND SALTS THEREOF RELATED CASE In our co-pending application, U.S. Ser. No. 229,558, filed Feb. 25, i972, now US. Pat. No. 3,825,590 the DL form of 3-hydroxymethyltyrosine is disclosed.

BACKGROUND OF THE INVENTION The compound 3-formyltyrosine is disclosed in Ger man Offenlegungsschrift No. 2,122,485.

SUMMARY OF THE INVENTION The compound L-3-hydroxymethyltyrosine may be represented by the following formula HO CH -TH-COOH The preferred method of preparing L-3-hydroxyme- 'mixture todryness. The resulting amide is dissolved in aqueous sodium hydroxide and dimethyl sulfate is added to form L-O-methyl-N-acctyltyrosine which is dissolved in an ethyalcohoI-chloroform solution, treated with p-toluenesulfonic acid and heated at reflux to form the corresponding ethyl ester. The ethyl ester of a'platinum oxide acetic anhydride cooc a NHcoc g isthen dissolved in methylene chloride, titanium tetrachloride and the solution chilled. To the chilled solution is added a,a-dichloromethyl methyl ether to form L-4-methoxy-3-formyl-N-acetyltyrosine ethyl ester. The thus obtained ethyl ester is reacted with a solution of boron trichloride in methylene chloride to form L-3-formyl-N-acetyltyrosine ethyl ester which upon treatment with 4 N hydrochloric acid forms L-3- formyltyrosine hydrochloride. The resulting compound is then treated with potassium carbonate to form the free base 3-formyltyrosine, which is dissolved in water and hydrogenated at 40 psi of hydrogen in the presence catalyst to form 'L- 3 -hydroxyme- 'thyl tyrosine. v,

1 The process may be illustrated as follows:

(cn so OCH EtOH OCH ' CHO COOC H NHCOCH COOH 1 ca oa The compound of the present invention may be employed as a'chelating agent in chemical processes in which it is desirable to inactivate heavy metal ions. es-

pecially ferric ions. The compound can simply be dissolved in warm water and added to the aqueous mixture containing the heavy metal ions in an amount cal- CHO COOCH CHO COOH

When employed as pharmaceutical agents, the novel amino acids are preferably combined with conventional pharmaceutical diluents, flavoring agents disintegrating and lubricant ingredients and formed into conventional oral unit dosage forms such as capsules, tablets and the like, and parenteral dosage forms such as solutions. Generally the tablets or capsules will contain 10 to 500 mg. of the active ingredients.

The number of tablets or capsules an individual patient may receive in a given 24 hour period will, of course, depend upon the amount of medication contained in the unit dosage form selected and the patient's condition.

The following examples illustrate the practice of the invention:

EXAMPLE I L O-Methyl-N-acetyltyrosine To a suspension of 45 g. (0.25 mole) tyrosine in 500 ml. water heated to 90 C. is added 190 ml. acetic anhy= dride dropwise over a 15 minute period. The heat is removed during the addition of the acetic anhydride. The solution is stirred an additional 15 minutes and concen= trated to dryness. The residue is dissolved in 140 ml. water containing 30 g. sodium hydroxide. To the solu= culated to be sufficient to inactivate the ions. in addition is slowly added 4l ml. dimethyl sulfate over a 30 tion, the compound L-3-hydroxymcthyltyrosine possesses antihypertensive activity.

Pharmaeeutically acceptable salts of the novel compounds may be prepared by reacting the amino acid in minute period. Toward the end of the addition. 40 ml. 10% sodium hydroxide is added to maintain basicity of the solution. The solution is stirred an additional 30 minutes, cooled. and acidified with concentrated hy= a suitable mutual solvent with an acid such as formic drochlorie acid. A gum which forms is extracted with acid, citric acid, malcie acid, sulfuric acid. hydrochlo= ric acid, succinic acid, tartaric acid. benzoic acid and fumaric acid.

chloroform. The organic solution is washed with water and dried and filtered. The chloroform phase is con= centrated to 250 ml. and refrigerated. The white solid which crystallizes has a m.p. of 142l45 C.

EXAMPLE 2 L-O-Methyl-N-acetyltyrosine ethyl ester A solution of 15 g. (0.063 mole) L-OmethylN- acetyltyrosine in 100 ml. ethanol and 400 ml. chloro form is charged with 1.0 g. p-toluenesulfonic acid and refluxed 15 hours, poured into H O, extracted with chloroform, washed with water and dried. Evaporation of solvent affords L-O-methyl-N-acetyltyrosine ethyl ester as a solid, m.p. 85-90 C.

EXAMPLE 3 L-4-Methoxy-3-formyl-N-acetyltyrosine ethyl ester To a chilled solution of 17.8 g. (0.067 mole) L-O-methyl-N-acetyltyrosine ethyl ester in 300 ml. methylene chloride is added dropwise 50 ml. titanium tetrachloride. A deep orange solution is obtained. To the chilled solution is added 20 ml. a,a-dichloromethyl methyl ether over a minute period. The solution is allowed to warm to room temperature and is stirred for 2 hours. The mixture is poured into 200 g. ice and 200 ml. 3N HCl and extracted with methylene chloride, washed with water and dried. Evaporation of solvent gives a semi-solid which on chromatography over silica gel gives purified L-4-methoxy-3-formyl-N- acetyltyrosine ethyl ester, m.p. 85 C.

EXAMPLE 4 L-3-Formyl-N-acetyltyrosine ethyl ester In 200 ml. cold methylene chloride is dissilved 29 g. boron trichloride to which is added 7.0 g. (0.0239 mole) L-4-methoxy-3-formyl-N-acetyltyrosine ethyl ester. The solution is stirred hours at room temperature during which time a green gum is deposited on the flask. Water (1000 ml.) is added dropwise to the reaction mixture. The organic layer is separated, washed with water, and dried. Evaporation of solvent gives a pink oil which is chromatographed over silica gel to give L-3-formylN-acetyltyrosine ethyl ester as a crystalline solid, m.p. 116 C.

EXAMPLE 5 L-3-Formyltyrosine hydrochloride 0 pink solid which is triturated with isopropanolzether to give L3-formyltyrosine hydrochloride as a solid.

EXAMPLE 6 L-3-Hydroxymethyltyrosine In 40 ml. water is dissolved 3.4204 g. (0.0139 mole) L-3-formyltyrosine hydrochloride. Potassium carbonate (0.965 g., 0.00697 mole) is added and the solution allowed to stand 15 hours. Yellow crystals of 3- formyltyrosine are obtained, collected and rinsed with 10 ml. cold water and 10 ml. isopropanol. The material is dried to give 2.28 g. (78%) yellow solid. The free amino acid is dissolved in 250 ml. water and hydrogenated over 0.3 g. platinum oxide at 40 psi hydrogen. After 1.5 hours the theoretical volume of hydrogen is absorbed. After filtering and concentrating the solvent to 20 ml., a white precipitate forms which is removed by filtration. The filtrate is allowed to evaporate to dryness and redissolved in 20 ml. water. The insoluble factor is again removed and the filtrate allowed to evaporate to dryness. Trituration with ethanol affords L-3-hydroxymethy'ltyrosine as a white solid which does not melt at 360: [0th, 30.49.

Anal. Calcd. for C H NO C, 56.86; H, 6.20; N, 6.63. Found: C, 56.93; H, 6.24; N, 6.54.

We claim:

1. A compound selected from L-3-hydroxymethyltyrosine and its pharmaceutically acceptable salts.

2. The compound of claim 1 which is L-3-hydroxymethyltyrosine. 

1. A COMPOUND SELECTED FROM L-3-HYDROXYMETHYLTYROSINE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS.
 2. The compound of claim 1 which is L-3-hydroxymethyltyrosine. 